GH4C1 cells are a clonal strain of rat pituitary tumor cells which secrete prolactin and growth hormone and which contain specific functional receptors for somatostatin and thyrotropin-releasing hormone (TRH). Preliminary experiments have demonstrated that the number of somatostatin receptors per cell can be modulated by TRH and by insulin but not by other hormones (e.g., LHRH or glucagon). We propose to: (1) Characterize the effects of insulin on somatostatin receptors in GH4C1 cells and compare the effects of insulin and TRH; prepare 125I-insulin and identify specific insulin receptors on GH4C1 cells and study the effects of somatostatin and TRH on the number of insulin receptors per cell and the affinity of these receptors for insulin; (3) Elucidate the nature and the sequence of events involved in the processing of bound (125I-Tyr1) somatostatin and the somatostatin-receptor complex after initial binding of the ligand; and (4) Determine whether these processing events can be modified by insulin and TRH and thereby elucidate the mechanism(s) by which these hormones specifically modulate the steady state concentration of somatostatin receptors on the cell surface. GH4C1 cells provide a uniquely useful system to study the mechanisms and the biological consequences of peptide hormone receptor modulation because they consist of a homogeneous cell population, because they contain specific functional receptors for several peptide hormones, and because the receptors for these hormones are subject to modulation both by homologous and heterologous ligands.